{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:56:48Z","timestamp":1770742608615,"version":"3.49.0"},"reference-count":62,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Italian Association for Cancer Research (AIRC)","doi-asserted-by":"publisher","award":["21588"],"award-info":[{"award-number":["21588"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1\/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2\/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2\u03b1 protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.<\/jats:p>","DOI":"10.3390\/ijms231810222","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T20:52:51Z","timestamp":1662497571000},"page":"10222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0268-5536","authenticated-orcid":false,"given":"Katia","family":"Grillone","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Riillo","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-7097","authenticated-orcid":false,"given":"Roberta","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"},{"name":"Net4Science s.r.l., Academic Spinoff, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Ascrizzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Span\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8149-7957","authenticated-orcid":false,"given":"Francesca","family":"Scionti","sequence":"additional","affiliation":[{"name":"Institute of Research and Biomedical Innovation (IRIB), Italian National Council (CNR), 98122 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicoletta","family":"Poler\u00e0","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6537-552X","authenticated-orcid":false,"given":"Annalisa","family":"Maruca","sequence":"additional","affiliation":[{"name":"Net4Science s.r.l., Academic Spinoff, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilia","family":"Barreca","sequence":"additional","affiliation":[{"name":"Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giada","family":"Juli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariamena","family":"Arbitrio","sequence":"additional","affiliation":[{"name":"Institute of Research and Biomedical Innovation (IRIB), Italian National Council (CNR), 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8205-2706","authenticated-orcid":false,"given":"Maria Teresa","family":"Di 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